title: Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells.
abstract: Angiogenesis is a key pathological feature of experimental and human steatohepatitis, a common chronic liver disease that is associated with obesity. We demonstrated that hepatocytes generated a type of membrane-bound vesicle, microparticles, in response to conditions that mimicked the lipid accumulation that occurs in the liver in some forms of steatohepatitis and that these microparticles promoted angiogenesis. When applied to an endothelial cell line, medium conditioned by murine hepatocytes or a human hepatocyte cell line exposed to saturated free fatty acids induced migration and tube formation, two processes required for angiogenesis. Medium from hepatocytes in which caspase 3 was inhibited or medium in which the microparticles were removed by ultracentrifugation lacked proangiogenic activity. Isolated hepatocyte-derived microparticles induced migration and tube formation of an endothelial cell line in vitro and angiogenesis in mice, processes that depended on internalization of microparticles. Microparticle internalization required the interaction of the ectoenzyme Vanin-1 (VNN1), an abundant surface protein on the microparticles, with lipid raft domains of endothelial cells. Large quantities of hepatocyte-derived microparticles were detected in the blood of mice with diet-induced steatohepatitis, and microparticle quantity correlated with disease severity. Genetic ablation of caspase 3 or RNA interference directed against VNN1 protected mice from steatohepatitis-induced pathological angiogenesis in the liver and resulted in a loss of the proangiogenic effects of microparticles. Our data identify hepatocyte-derived microparticles as critical signals that contribute to angiogenesis and liver damage in steatohepatitis and suggest a therapeutic target for this condition.
authors.affiliation: 1Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Povero
authors.forename: Akiko
authors.initials: A
authors.lastname: Eguchi
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Niesman
authors.forename: Nektaria
authors.initials: N
authors.lastname: Andronikou
authors.forename: Xavier
authors.initials: X
authors.lastname: de Mollerat du Jeu
authors.forename: Anny
authors.initials: A
authors.lastname: Mulya
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.forename: Milos
authors.initials: M
authors.lastname: Lazic
authors.forename: Samjana
authors.initials: S
authors.lastname: Thapaliya
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats
chemical_list: D017077:Culture Media, Conditioned; D005230:Fatty Acids, Nonesterified; D058851:GPI-Linked Proteins; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D000581:Amidohydrolases; C022314:pantetheinase